OBJECTIVES: To assess the change in general health-related quality of life (HRQoL) of multiple sclerosis (MS) patients after one year of natalizumab treatment.  METHODS: MS patients, newly starting natalizumab, were recruited to participate in a longitudinal observational study to assess general health-related quality of life using the SF-12v2 prior to natalizumab initiation and after the 3rd, 6th and 12th infusions. Higher physical component summary scores (PCS) and mental component summary scores (MCS) on the SF-12v2 indicate better HRQoL. Statistical regression models were used to evaluate changes in PCS and MCS scores from baseline through the 12th infusion after controlling for baseline patient-level and treatment characteristics.  RESULTS: Data for 192 patients who had completed the baseline through 12th infusion assessments of this ongoing study are reported. The mean age was 46.09 (SD=10.78) and the majority of patients were female (78%). The mean number of years since MS diagnosis was 10.16 (SD=8.23). The PCS score improved significantly from baseline (BL 33.30±7.12, 12th infusion 35.91±7.12; p<0.001); similar improvements were observed in the MCS scores which also improved significantly from baseline (BL 43.12±1.53, 12th infusion 47.95±1.53; p<0.001).  CONCLUSIONS: Patients reported improvements in general HRQoL measures after one year of natalizumab treatment in the usual care setting. These results are consistent with results from pivotal clinical trials and document the beneficial impact of natalizumab on HRQoL of MS patients.